This invention is generally in the field of anesthesiology and, in particular, the delivery of anesthetic agents which locally block pain for periods of time of between a few hours and days, up to weeks.
In order to provide local or regional blockade for extended periods, clinicians currently use local anesthetics administered through a catheter or syringe to a site where the pain is to be blocked. This requires repeated administration where the pain is to be blocked over a period of greater than one day, either as a bolus or through an indwelling catheter connected to an infusion pump. These methods have the disadvantage of potentially causing irreversible damage to nerves or surrounding tissues due to fluctuations in concentration and high levels of anesthetic. In addition, anesthetic administered by these methods are generally neither confined to the target area, nor delivered in a linear, continuous manner. In all cases, analgesia rarely lasts for longer than six to twelve hours, more typically four to six hours. In the case of a pump, the infusion lines are difficult to position and secure, the patient has limited, encumbered mobility and, when the patient is a small child or mentally impaired, may accidentally disengage the pump.
Drugs are typically administered in a variety of ways, including by injection, topical administration, oral ingestion, and sustained release devices. Methods which provide for systemic, rather than localized, delivery are not an option with local anesthetics since these could interfere with the patient's ability to breathe, if administered systemically. Devices could potentially provide for a sustained, controlled, constant localized release for longer periods of time than can be achieved by injection or topical administration. These devices typically consist of a polymeric matrix or liposome from which drug is released by diffusion and/or degradation of the matrix. The release pattern is usually principally determined by the matrix material, as well as by the percent loading, method of manufacture, type of drug being administered and type of device, for example, microsphere. A major advantage of a biodegradable controlled release system over others is that it does not require the surgical removal of the drug depleted device, which is slowly degraded and absorbed by the patient's body, and ultimately cleared along with other soluble metabolic waste products.
Systemic anesthetics such as methoxyflurane, have been incorporated into liposomes and lecithin microdroplets, for example, as described by Haynes, et al., Anesthesiology 63:490-499 (1985). To date, the liposome and lecithin preparations have not been widely applied in clinical or laboratory practice, because of their inability to provide dense blockade for a prolonged period of time (i.e., three or more days) in a safe and controlled manner. The lecithin microdroplets and liposomes degrade or are phagocytized too rapidly, in a matter of hours. Other lipid based devices, formed in combination with polymer, for release of local anesthetics are described by U.S. Pat. No. 5,188,837 to Domb.
Local anesthetics have been incorporated into biodegradable polymeric devices, for example, polylactic acid microspheres, as described by Wakiyama, et al., Chem. Pharm. Bull., 30:3719-3727 (1982). In contrast to the lipid based materials, the poly(lactic acid) devices take over a year to degrade and cause localized inflammation. Berde, et al., Abstracts of Scientific Papers, 1990 Annual Meeting, Amer. Soc. Anesthesiologists, 73:A776 (September 1990), reported the use of a device formed of a polyanhydride polymer matrix of copolymer 1,3 bis(p-carboxyphenoxy)propane and sebacic acid, in a ratio of 1:4, into which dibucaine free base was incorporated by compression molding. This drug-polymer device, however, had several drawbacks. For example, because the drug was incorporated into the polymer matrix by compression molding, the device sometimes displayed bulk erosion, causing fast initial release of drug. In addition, the device often generated an inflammatory response or a capsule of serous material or fibrin, which is particularly a problem when located adjacent to nerves.
Other studies have reported encapsulation of local anesthetics such as bupivacaine or tetracaine in polyanhydride or poly-lactic-glycolic acid polymeric microspheres, Masters (1993), Masters (1993), and Lim (1995). Sensory and motor blockade in these studies lasted for periods of one to ten days, depending on the type of preparation and dose used. While implantable, the microspheres were not small enough to inject.
Accordingly, it is the object of this invention to provide an improved biodegradable controlled release device which administers local anesthetic for a prolonged period of time which is injectable.
It is a further object of the present invention to provide a method and means for modulating the rate of release of the local anesthetic from the bioerodible polymer matrix through variations in microsphere composition and size.